Cathepsin S is mainly a lysosomal cysteine protease that is expressed on antigen-presenting cells such as dendritic cells, macrophages, and B-cells, and plays a role in the degradation of an invariant chain bonded when major histocompatibility gene complex class II (MHC class II) molecules are generated. MHC class II molecules are bonded to self-peptide or non-self peptide taken from the outside of a cell, and by presenting the non-self peptide or pathogenic self-peptide to CD4 positive T cells, secretion of various cytokines is induced. It is confirmed that by inhibiting cathepsin S or making cathepsin S deficient, loading of antigenic peptide to MHC class II molecules are inhibited, and antigen presentation to CD4 positive T cells is suppressed, and by these, an immune response with respect to a foreign antigen is decreased (Nakagawa et al, Immunity, 1999, Vol. 10, No. 2, pp. 207-217).
In this respect, an inhibitor of cathepsin S can be useful as an agent for preventing and/or treating inflammation and immune disease such as rheumatoid arthritis, multiple sclerosis, SLE, psoriasis and Crohn's disease, and as an agent for preventing and/or treating graft rejection.
It have been reported that the compounds represented by the following formulas (A) (Patent Documents 1 and 2), (B) (Patent Document 3), (C) (Patent Document 4), and (D) (Patent Document 5) exhibit cathepsin S inhibition, and are useful as an agent for treating inflammations such as rheumatismimmune disorders and the like. It have been reported that the compound represented by the following formula (E) exhibits cathepsin S inhibition, and is useful as an agent for treating inflammations such as rheumatismimmune disorders and the like (Patent Document 6).
(Refer to this publication for the symbols in the formulas (A) to (D). In the formula (E), R is aryl or hetero aryl which may be substituted with a halogen or the like, H, C1-6 alkyl, or C3-6 cycloalkyl, Y is N, CH, or the like, R1 is Y(CH2)pR7, Y in Y(CH2)pR7 is O or NR8, and R7 is a 5 to 6-membered saturated heterocycle.)